1. Field of the Invention
The present invention relates to novel sialocylglycerolipids as alkali metal salts of sialic acid-containing lipid derivatives and a method for preparing the same.
2. Description of the Prior Art
In general, most of the diseases resulting from neuropathy are considered to be difficult to treat or cure. In addition, a rather small number of therapeutic agents therefore have been developed.
Examples thereof which are clinically tried at present are naturally occurring gangliosides (sold under the trade name of Cronassial; see Japanese Patent Un-examined Publication (hereunder referred to as "J.P. KOKAI") No. 52-34912) and mecobalamin (general name of medicine) which is a vitamins. However, they do not have a satisfactory effect on these diseases and, therefore, there is a demand for the development of further improved therapeutic agents.
In addition, acidic glycolipids such as ganglioside and such acidic phospholipids such as phosphatidyl inositol and phosphatidyl serine are known which play an important roles in neurotransmitting systems of animals. The inventors of this invention have found that a mixture of gangliosides or a single component present in a ganglioside promotes the proliferation of primarily cultured nerve cells and neuroblastoma cells and promotes the formation of neurites and the extensions thereof. Further, they exhibit an effect similar to that of mecobalamin in animal models and one of the inventors already filed a patent application (see J.P. KOKAI No. 59-222424).
As already discussed above, the ganglioside mixtures are, for the present, used in the treatment of peripheral nerve disorders or central nerve disorders. However, since these gangliosides are natural products extracted from different animals, a problem of antigenicity due to the gangliosides per se or impurities arises.
Besides, it is very difficult to establish a strict standard therefore since they are not necessarily pharmaceutically stable and uniform.
On the other hand, sialic acid present in these gangliosides is also found in, for instance, glycoproteins or exists in cell surfaces of animals or bacteria. Recently, they are attracting much attention from the medical and pharmacologic viewpoint as materials involved in immunity, cancer, inflammation, various infections, cell differentiation, hormone receptors and the like. There is no report on the therapeutic effects of sialic acid-containing lipid derivatives on nerve disorders.
Taking this fact into consideration, the inventors of the present invention found that a sialocylglycerolipid, which is a sodium salt of a derivative of a sialic acid-containing lipid, i.e., (3-0-(sodium-(5-acetamido-3,5-dideoxy-alpha-D-glycero-D-galacto-2-nonulopy ranosyl) -onato)-1,2-di-0-tetradecyl-Sn-glycerol) shows a neurite extention effect and that it might suitably be used in improving or treating nerve diseases (see Japanese Patent Application Serial (hereunder referred to as "J.P.A.") No. 61-214787).
It would be expected that other sialocylglycerolipids likewise might show an effect similar to the aforementioned offset, but the synthesis of such a lipid has not yet been reported.
Japanese Patent Publication for Opposition Purpose (hereunder referred to as "J.P. KOKOKU") No. 59-164798 discloses that a variety of derivatives of sialic acid can be obtained by converting sialic acid to a sugar donor according in a known method and then reacting it with a sugar acceptor which is likewise obtained in a known manner.
However, this method proceeds in accordance with the following processes and thus improvements must be made on many points. ##STR2## wherein Ac represents an acetyl group.
More specifically, the above mentioned method comprises dissolving Compound (IV) in methanol, adding 1N NaOCH.sub.3 thereto, stirring the solution at room temperature for one hour, then neutralizing the solution with Amberlist A-15 (trade mark) followed by filtering the same, concentrating it under a reduced pressure to precipitate Compound (V) in a yield of 67%. However, in this method, the yield of the desired product is very low and the product must further undergo the following three steps to provide compound (VI) which is effective for treating nervous diseases. ##STR3##
In order to solve these problems accompanied by the conventional method, the inventors of the present invention developed the following method and filed a patent application relating to such a method (J.P.A. No. 61-189340). This method comprises hydrolyzing a compound represented by the following general formula (VII): ##STR4## wherein Ac is the same as defined above and R represents a lower alkyl group, in a solution of sodium hydroxide in ROH or an aqueous solution of tetrahydrofuran (THF) and then separating and purifying the product by reverse phase column chromatography to recover a compound represented by the following general formula (VI): ##STR5## wherein Ac is the same as defined above.
However, at the time of filing the aforementioned patent application, the kind of molecules to which this method for preparing sialocylglycerolipids having high biological activity can be applied (see J.P.A. No. 61-214787) was still unclear and solvents which could be used in the reaction were not specified.